US6924302B2 - Substituted triazole diamine derivatives as kinase inhibitors - Google Patents

Substituted triazole diamine derivatives as kinase inhibitors Download PDF

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US6924302B2
US6924302B2 US10/029,750 US2975001A US6924302B2 US 6924302 B2 US6924302 B2 US 6924302B2 US 2975001 A US2975001 A US 2975001A US 6924302 B2 US6924302 B2 US 6924302B2
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alkyl
amino
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thienyl
substituted
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US20040077699A1 (en
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Ronghui Lin
Peter J. Connolly
Steven K. Wetter
Shenlin Huang
Stuart L. Emanuel
Robert H. Gruninger
Steven A. Middleton
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Janssen Pharmaceuticals Inc
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Ortho McNeil Pharmaceutical Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention provides substituted triazole diamine derivatives as selective kinase or dual-kinase inhibitors and a method of use thereof. More particularly, the present invention provides substituted 1,2,4-triazole-3,5-diamine derivatives as selective kinase or dual-kinase inhibitors and a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder.
  • Patent application WO 99/21845 describes 4-aminothiazole derivatives as inhibitors of cyclin dependent kinases of the formula: wherein R 1 is a substituted or unsubstituted group selected from: C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl); C 1-6 -alkenyl; C 1-6 -alkynyl; C 1-6 -alkoxyl; C 1-6 -alcohol; carbocyclic or heterocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidiny
  • Patent application WO 01/09106 describes diamino-1,2,4-triazole-carboxylic and derivatives as GSK-3 (glycogen synthase kinase) inhibitors of formula (I): wherein the R 3 CZ-moiety may be attached to the nitrogen atom at position I or the nitrogen atom at position 2; R 1 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic; R 2 is hydrogen, alkyl, aryl, aralkyl, aralkenyl or alicyclic, or R 1 and R 2 together with the nitrogen atom to which they are attached may form a heterocyclic ring which ring may be unsubstituted or substituted; R 3 is alkyl, aryl, aralkyl, aryl(Q)alkyl, where Q is O or S, aralkenyl, alicyclic, heteroaryl, heteroaralkyl, arylcarbonylalky
  • R 1 is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy(C 1 -C 6 )alkyl, aryl, aryloxy, halo, hydroxy, carboxy, cyano, and nitro.
  • R 1 is phenyl either unsubstituted or substituted with up to three of methyl, methoxy, or chloro.
  • R 2 is hydrogen or unsubstituted or substituted phenyl, wherein the substituents for the phenyl group are independently selected from up to three of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy(C 1 -C 6 )alkyl, aryl, aryloxy, halo, hydroxy, carboxy, cyano, and nitro.
  • R 2 is hydrogen.
  • R 3 is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted benzyl, unsubstituted or substituted thienylmethyl, unsubstituted or substituted phenylthiomethyl, unsubstituted or substituted naphthylmethyl, unsubstituted or substituted furylethenyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted pyridyl, unsubstituted or substituted indolylmethyl, unsubstituted or substituted phenylcarbonylethyl, unsubstituted or substituted cyclopentenylmethyl, unsubstituted or substituted phenylpropyl, unsubstituted or substituted diphenylethyl, wherein the substituents for the R 3 aryl groups are selected from —O
  • R 3 is phenyl either unsubstituted or substituted with up to three of chloro, bromo, phenyl, trifluoromethyl, nitro, benzoyl, phenoxy, acetyl, or 3,4-OCH 2 O—; naphthyl; benzyl either unsubstituted or substituted with up to three of phenyl or fluoro; 2-thienylmethyl; phenylthiomethyl 2-naphthylmethyl; cyclohexyl; 3-pyridyl; 3-indolylmethyl; phenylcarbonylethyl; cyclopent-2-enylmethyl; phenylpropyl; 2,2-diphenylethyl; or 2-furylethenyl; or NR 6 R 7 where R 6 and R 7 are each independently hydrogen, phenyl either unsubstituted or substituted with up to three of chloro, phenyl, phenoxy, methyl, brom
  • R 4 is hydrogen.
  • R 5 is hydrogen.
  • R 6 is unsubstituted or substituted aryl or unsubstituted or substituted alicyclic.
  • R 6 is cyclohexyl, naphthyl or phenyl which phenyl group may be either unsubstituted or substituted with up to three of chloro, bromo, phenyl, methyl, phenoxy, nitro or methoxy.
  • R 7 is hydrogen.
  • substituted triazole diamine derivatives as selective kinase or dual-kinase inhibitors and a method of use thereof. It is an object of the present invention to provide substituted 1,2,4-triazole-3,5-diamine derivatives as selective kinase or dual-kinase inhibitors and a method of use for treating or ameliorating a selective kinase or dual-kinase mediated disorder.
  • the present invention provides a compound of Formula (I): wherein
  • An embodiment of the present invention is a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder.
  • An embodiment of the present invention includes a method for producing the instant compounds and pharmaceutical compositions and medicaments thereof.
  • Embodiments of the present invention include compounds of Formula (I) wherein, preferably, R 1 is selected from the group consisting of: C 1-4 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl (wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with a substituent selected from the group consisting of:
  • R 1 is selected from the group consisting of C 1-4 alkyl and aryl ⁇ wherein aryl is substituted with a substituent selected from the group consisting of:
  • R 1 is selected from the group consisting of C 1-4 alkyl and phenyl ⁇ wherein phenyl is substituted with a substituent selected from the group consisting of: amino (substituted with two substituents independently selected from the group consisting of:
  • Embodiments of the present invention include compounds of Formula (I) wherein, preferably, R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and hydroxy(C 1-4 )alkyl.
  • R 2 is selected from the group consisting of hydrogen and C 1-4 alkyl.
  • R 2 is hydrogen
  • Embodiments of the present invention include compounds of Formula (I) wherein, preferably, X is selected from the group consisting of —C(O)—, —C(S)— and —SO 2 —.
  • Embodiments of the present invention include compounds of Formula (I) wherein, preferably, R 3 is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 1 is selected from the group consisting of:
  • Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Ia): wherein
  • Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Ib): wherein
  • Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Ic): wherein
  • Embodiments of the present invention include compounds of Formula (Ic) wherein, preferably, R 4 is selected from the group consisting of:
  • Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Id): wherein
  • Embodiments of the present invention include compounds of Formula (I) selected from a compound of Formula (Ie): wherein
  • Exemplified compounds of the present invention include a compound of Formula (I) selected from a compound of Formula (Ic): wherein X, R 2 , R 3 and R 4 are dependently selected from:
  • Exemplified compounds of the present invention include a compound of Formula (I) selected from a compound of Formula (Id): wherein X, R 3 and R 4 are dependently selected from:
  • Exemplified compounds of the present invention include a compound of Formula (I) selected from a compound of Formula (Ie): wherein R 1 and R 3 are dependently selected from:
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts” ( Ref. International J. Pharm ., 1986, 33, 201-217 ; J. Pharm.Sci ., 1997 (January), 66, 1, 1).
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid.
  • Organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds, which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “ Design of Prodrugs ”, ed. H. Bundgaard, Elsevier, 1985.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by standard techniques known to those skilled in the art, for example, by enantiospecific synthesis or resolution, formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention and moreover that the term “a compound of Formula x” will encompass a compound's enantiomers, diastereomers, and the like.
  • alkyl refers to a saturated straight or branched chain consisting solely of 1-8 hydrogen substituted carbon atoms; preferably, 1-6 hydrogen substituted carbon atoms; and, most preferably, 1-4 hydrogen substituted carbon atoms.
  • alkenyl refers to a partially unsaturated straight or branched alkyl chain that contains at least one double bond.
  • alkynyl refers to a partially unsaturated straight or branched alkyl chain that contains at least one triple bond.
  • alkoxy refers to —O-alkyl, where alkyl is as defined supra.
  • cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl ring consisting of 3-8 hydrogen substituted carbon atoms. Examples include, and are not limited to, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • heterocyclyl refers to a saturated or partially unsaturated ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O atom or one, two or three additional N atoms; a saturated or partially unsaturated ring having six members of which one, two or three members are a N atom; a saturated or partially unsaturated bicyclic ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms; and, a saturated or partially unsaturated bicyclic ring having ten members of which one, two or three members are a N atom.
  • Examples include, and are not limited to, pyrrolinyl, pyrrolidinyl, dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl or piperazinyl.
  • aryl refers to an aromatic monocyclic ring system containing 6 hydrogen substituted carbon atoms, an aromatic bicyclic ring system containing 10 hydrogen substituted carbon atoms or an aromatic tricyclic ring system containing 14 hydrogen substituted carbon atoms. Examples include, and are not limited to, phenyl, naphthalenyl or anthracenyl.
  • heteroaryl refers to an aromatic monocyclic ring system containing five members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms, an aromatic monocyclic ring having six members of which one, two or three members are a N atom, an aromatic bicyclic ring having nine members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms and an aromatic bicyclic ring having ten members of which one, two or three members are a N atom.
  • Examples include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, quinolinyl or isoquinolinyl.
  • halo or halogen refers to a fluoro, chloro, bromo or iodo atom.
  • An embodiment of the invention is a pharmaceutical composition or medicament comprising a pharmaceutically acceptable carrier and any of the compounds described above.
  • Illustrative of the invention is a pharmaceutical composition or medicament made by mixing any of the compounds described above and a pharmaceutically acceptable carrier.
  • Another illustration of the invention is a process for making a pharmaceutical composition or medicament comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
  • Further illustrative of the present invention are pharmaceutical compositions or medicaments comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the compounds of the present invention are selective kinase or dual-kinase inhibitors useful in a method for treating or ameliorating a kinase or dual-kinase mediated disorder.
  • the kinase is selected from a cyclin dependent kinase and a tyrosine kinase. More particularly, the kinase is selected from cyclin dependent kinase-1, cyclin dependent kinase-2, cyclin dependent kinase-4, vascular endothelial growth factor receptor-2, endothelial growth factor receptor or human epidermal growth factor receptor-2.
  • Cyclin-dependent kinase inhibitors play a critical role in regulating progression of the eukaryotic cell through the cell cycle by associating with protein complexes composed of cyclins and cyclin-dependent kinases and thus down-regulating the activity of the cyclin-dependent kinases.
  • Pathways involving cyclin-dependent kinase inhibitors are frequently disrupted in tumor cells leading to abnormal regulation of the cell cycle.
  • Overexpression of cyclin-dependent kinase inhibitors leads to arrest of cells at one of the check points in the cell cycle. Therefore, using cyclin-dependent kinase inhibitors for tumor therapy is intuitively attractive because it has the potential for tumour growth.
  • CDK-1 receptor This protein controls the last checkpoint in the cell cycle between the G2 and M phase.
  • VEGF vascular endothelial growth factor
  • VEGF-R2 KDR/Flk1/VEGF-R2
  • VEGF-R1 Flt1/VEGF-R1
  • VEGF-R2 signalling has been shown to inhibit the process of angiogenesis. Inhibitors of this receptor are likely useful in controlling or limiting angiogenesis.
  • cytotoxic cancer therapies destroy the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss).
  • Inhibition of cyclin dependent kinases may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia by arresting the cell cycle and reducing the sensitivity of epithelial cells to antitumor agents (Davis S. T., etal., Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors, Science , 2001, (January 5), 291, 5501, 25-6).
  • Topical application of non-apoptotic CDK inhibitors represents a potentially useful approach for the prevention of chemotherapy-induced alopecia in cancer patients.
  • Embodiments of the method of the present invention include a method for treating or ameliorating a selective kinase or dual-kinase mediated disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an instant compound or pharmaceutical composition thereof.
  • the therapeutically effective amount of the compounds of Formula (I) exemplified in such a method is from about 0.001 mg/kg/day to about 300 mg/kg/day.
  • Embodiments of the present invention include the use of a compound of Formula (I) for the preparation of a medicament for treating or ameliorating a kinase or dual-kinase mediated disorder in a subject in need thereof.
  • an individual compound of the present invention or a pharmaceutical composition thereof can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term “administering” is to be interpreted accordingly.
  • Embodiments of the present method include a compound or pharmaceutical composition thereof advantageously co-administered in combination with other agents for treating or ameliorating a kinase or dual-kinase mediated disorder.
  • the combination product comprises co-administration of a compound of Formula (I) or pharmaceutical composition thereof and an additional agent for treating or ameliorating a kinase or dual-kinase mediated disorder, the sequential administration of a compound of Formula (I) or pharmaceutical composition thereof and an additional agent for treating or ameliorating a kinase or dual-kinase mediated disorder, administration of a pharmaceutical composition containing a compound of Formula (I) or pharmaceutical composition thereof and an additional agent for treating or ameliorating a kinase or dual-kinase mediated disorder or the essentially simultaneous administration of a separate pharmaceutical composition containing a compound of Formula (I) or pharmaceutical composition thereof and a separate pharmaceutical composition containing an additional agent for treating or ameliorating a kinase or dual-kinase mediated disorder.
  • other agents includes, and is not limited to, anti-angiogenic agents, anti-tumor agents, cytotoxic agents, inhibitors of cell proliferation, and the like.
  • treating or ameliorating includes, and is not limited to, facilitating the eradication of, inhibiting the progression of or promoting stasis of a malignancy.
  • a dual CDK1-VEGF-R inhibitor compound of the present invention, acting as an anti-angiogenic agent can be administered in a dosing regimen with at least one other cytotoxic compound, such as a DNA alkylating agent.
  • Preferred anti-tumor agents are selected from the group consisting of cladribine (2-chloro-2′-deoxy-(beta)-D-adenosine), Chlorambucil (4-[bis(2-chlorethyl)amino]benzenebutanoic acid), DTIC-Dome (5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide), platinum chemotherapeutics and nonplatinum chemotherapeutics.
  • Platinum containing anti-tumor agents include, but are not limited to, cisplatin (cis-dichlorodiamineplatinum).
  • Non-platinum containing anti-tumor agents include, but are not limited to, cyclophosphamide, fluorouracil, epirubicin, methotrexate, vincristine, doxorubicin, bleomycin, and etoposide.
  • Each anti-tumor agent is administered in a therapeutically effective amount, which varies based on the agent used, the type of malignancy to be treated or ameliorated and other conditions, according to methods well known in the art.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • a compound of Formula (I) is therapeutically effective for certain kinase or dual-kinase mediated disorders based on the modulation of the disorder by selective kinase or dual-kinase inhibition.
  • the activity of the instant compounds as selective kinase or dual-kinase inhibitors is derived from the novel combination of the structural elements X, R 3 and R 4 optimally substituted on the triazole scaffold.
  • the usefulness of a compound of Formula (I) as a selective kinase or dual-kinase inhibitor can be determined according to the methods disclosed herein and the scope of such usefulness includes use in one or more kinase or dual-kinase mediated disorders.
  • kinase or dual-kinase mediated disorders includes, and is not limited to compounds capable of inhibiting one or more kinases where knase inhibition is also associated with cancers, abnormal cell proliferation, tumor growth, tumor vascularization, as well as angiopathy, angiogenesis, chemotherapy-induced alopecia and restenosis.
  • the compounds of this invention are useful as an adjunct to a variety of chemotherapeutic agents that are recommended for specific cancer therapy regimes.
  • the compounds of this invention have been demonstrated to be useful in combination therapies with at least one other chemotherapeutic agent for the treatment of a number of different cancers and advantageously appears to facilitate the use of a reduced dose of the chemotherapeutic agent that is recommended for a particular cancer or cell proliferation disorder. Therefore, it is contemplated that the compounds of this invention can be used in a treatment regime before the administration of a particular chemotherapeutic agent recommended for the treatment of a particular cancer, during admninstration of the chemotherapeutic agent or after treatment with a particular chemotherapeutic agent.
  • compositions contemplated within this invention can be prepared according to conventional pharmaceutical techniques.
  • a pharmaceutically acceptable carrier may be used in the composition of the invention.
  • the composition may take a wide variety of forms depending on the form of preparation desired for administration including, but not limited to, intravenous (both bolus and infusion), oral, nasal, transdermal, topical with or without occlusion, intraperitoneal, subcutaneous, intramuscular or parenteral, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • one or more of the usual pharmaceutical carriers may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, syrup and the like in the case of oral liquid preparations (for example, suspensions, elixirs and solutions), or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (for example, powders, capsules and tablets).
  • oral liquid preparations for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (for example, powders, capsules and tablets).
  • the compounds may alternatively be administered parenterally via injection of a formulation consisting of the active ingredient dissolved in an inert liquid carrier.
  • the injectable formulation can include the active ingredient mixed with an appropriate inert liquid carrier.
  • Acceptable liquid carriers include vegetable oils such as peanut oil, cotton seed oil, sesame oil, and the like, as well as organic solvents such as solketal, glycerol, formal, and the like.
  • aqueous parenteral formulations may also be used.
  • acceptable aqueous solvents include water, Ringer's solution and an isotonic aqueous saline solution.
  • a sterile non-volatile oil can usually be employed as solvent or suspending agent in the aqueous formulation.
  • the formulations are prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.005 to 10% by weight of the active ingredient.
  • Other additives including a preservative, an isotonizer, a solubilizer, a stabilizer and a pain-soothing agent may adequately be employed.
  • compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • tablets and capsules represent an advantageous oral dosage unit form, wherein solid pharmaceutical carriers are employed. If desired, tablets may be sugarcoated or enteric-coated by standard techniques.
  • the active drug component can be combined in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, including for example, tragacanth, acacia, methyl-cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, including for example, tragacanth, acacia, methyl-cellulose and the like.
  • Other dispersing agents include glycerin and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes containing delivery systems as well known in the art are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the instant pharmaceutical composition will generally contain a per dosage unit (e.g., tablet, capsule, powder, injection, teaspoonful and the like) from about 0.001 to about 100 mg/kg.
  • the instant pharmaceutical composition contains a per dosage unit of from about 0.01 to about 50 mg/kg of compound, and preferably from about 0.05 to about 20 mg/kg.
  • Methods are known in the art for determining therapeutically effective doses for the instant pharmaceutical composition.
  • the therapeutically effective amount for administering the pharmaceutical composition to a human for example, can be determined mathematically from the results of animal studies.
  • Cpd Compound “CSCl 2 ” thiophosgene “DIC” diisopropyl carbodiimide “DMF” N,N-dimethylformamide “EDCI” ethyl dimethylaminopropyl carbodiimide “HOBT” hydroxybenzyl triazole “NH 2 NH 2 ” hydrazine “Pd” palladium(II) “Ph” phenyl “rt” room temperature “TBAF” tetrabutylammonium fluoride “TFA” trifluoroacetic acid “THF” tetrahydrofuran
  • Names can be generated using a nomenclature system based on this example, or may be generated using commercial chemical naming software such as ACD/Index Name (Advanced Chemistry Development, Inc., Toronto, Ontario).
  • Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and are illustrated more particularly in the schemes that follow. Since the schemes are illustrations, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art.
  • Compound A4 was dissolved in a suitable solvent and reacted with R 3 CO 2 H or R 3 COCl (wherein R 3 is as previously defined) and a coupling reagent such as DIC (diisopropyl carbodiimide) or EDCI (ethyl dimethylaminopropyl carbodiimide) to yield the target Compound A5.
  • a coupling reagent such as DIC (diisopropyl carbodiimide) or EDCI (ethyl dimethylaminopropyl carbodiimide)
  • Compound B3 was prepared according to published procedure (as described in Webb, R. L., Eggleston, D. S. and Labaw, C. S., J. Heterocyclic Chemistry , 1987, 24, 275-278). Following the procedure of Scheme A, Compound B3 was reacted with hydrazine to produce the target intermediate Compound A4.
  • Compound C1 (CAS # 1455-77-2) was dissolved in a suitable solvent and reacted with R 3 CO 2 H or R 3 COCl (wherein R 3 is as previously defined) and a coupling reagent such as DIC or EDCI to yield the Compound C2.
  • Compound C2 was purified, dissolved in a suitable solvent and reacted in an inert atmosphere with R 1 -halo (wherein R 1 and halo are as previously defined; in addition to halo, R 1 may be coupled with another suitable leaving group) in the presence of a base, such as potassium carbonate, and a catalyst, such as a palladium complex.
  • the product Compound A5 was isolated using conventional means.
  • Compound D1 (CAS# 24807-56-5) was dissolved in a suitable solvent and reacted with R 1 NH 2 in the presence of a base such as potassium carbonate, and a catalyst such as a palladium complex to yield the Compound D2.
  • Compound D2 was purified, dissolved in a suitable solvent and subjected to catalytic hydrogenation to give Compound A4.
  • Compound A4 may then be used to produce other target compounds of the invention as described in Scheme A.
  • Compound A3 was dissolved in a solvent and reacted with a protecting group such as a substituted benzyl halide (for example, 4-methoxybenzyl bromide) in the presence of a base (such as potassium carbonate) to yield a Compound E1.
  • a protecting group such as a substituted benzyl halide (for example, 4-methoxybenzyl bromide)
  • a base such as potassium carbonate
  • Compound E1 was purified, dissolved in a suitable solvent and then reacted with R 2 -halo (wherein R 2 and halo are as previously defined; in addition to halo, R 2 may be coupled with another suitable leaving group) in the presence of a base (such as potassium carbonate) to give a Compound E2.
  • R 2 -halo wherein R 2 and halo are as previously defined; in addition to halo, R 2 may be coupled with another suitable leaving group
  • a base such as potassium carbonate
  • test compound stock in 100% DMSO was added to the wells resulting in a final concentration of 1% DMSO in the reaction with a 100 ⁇ l final reaction volume.
  • the histone-H1 biotinylated peptide substrate became immobilized on the FlashplateTM and the incorporation of 33 P- ⁇ -ATP was measured by reading the plate on a scintillation counter. Inhibition of the enzymatic activity of CDK1 was measured by observing a reduced amount of 33 P- ⁇ -ATP incorporated into the immobilized peptide.
  • test compound stock in 100% DMSO was added to the wells resulting in a final concentration of 1% DMSO in the reaction with a 100 ⁇ L final reaction volume.
  • the PLC1 biotinylated peptide substrate became immobilized on the FlashplateTM and the incorporation of 33 P- ⁇ -ATP was measured by reading the plate on a scintillation counter. Inhibition of the enzymatic activity of the VEGF-R was measured by observing a reduced amount of 33 P- ⁇ -ATP incorporated into the immobilized peptide.
  • IC 50 data for VEGF-R and CDK are shown in Table 1. IC 50 values listed as >10 or >100 indicate no observed 50% inhibition at the highest dose tested, nor was an inhibition maxima observed. ND means not tested.
  • Biotinylated peptide substrates were selected from the literature as appropriate for the enzyme being evaluated.
  • Assay conditions vary slightly for each protein kinase, for example, insulin receptor kinase requires 10 mM MnCl 2 for activity and Calmodulin-dependent protein kinase requires calmodulin and 10 mM CaCl 2 .
  • the reaction mixture was dispensed into the wells of a streptavidin coated Flashplate and 1 ⁇ l drug stock in 100% DMSO was added to a 100 ⁇ l reaction volume resulting in a final concentration of 1% DMSO on the reaction.
  • test compounds were assayed in duplicate at 8 concentrations [100 uM, 10 uM, 1 uM, 100 nM, 10 nM, 1 nM, 100 pM, 10 pM]. A maximum and minimum signal for the assay was determined on each plate.
  • Known inhibitor compounds appropriate for the kinase being assayed were also included on each plate.
  • VEGF-R vascular endothelial growth factor receptor-2
  • CDK1 cyclin dependent kinase 1
  • CDK2 in complex with cyclin A is commercially available (Upstate Biotech, Lake Placid, N.Y.).
  • the CDK4 complex was composed of a mouse CDK4 protein and a mouse Cyclin D1 protein (The mouse CDK4 protein was genetically fused to an N-terminal Flag-epitope tag and the mouse Cyclin D1 protein was fused with an N-terminal AU-1 epitope tag. The genes encoding these proteins were transferred to commercially available baculoviral vectors. The recombinant CDK4/D1 complex was then made by co-infecting commercially available insect cells with viruses carrying these two constructs).
  • Insulin Receptor Kinase consists of residues 941-1313 of the cytoplasmic domain of the beta-subunit of the human insulin receptor (BIOMOL, Plymouth Meeting, Pa., Cat. #SE-195).
  • Protein Kinase A is the catalytic subunit of cAMP dependent protein kinase-A purified from bovine heart (Upstate Biotech, Lake Placid, N.Y., Cat#14-114).
  • PKC protein kinase-C
  • Casein Kinase 1 is a truncation at amino acid 318 of the C-terminal portion of the rat CK1 delta isoform produced in E. coli (New England Biolabs, Beverly, Mass., Cat. #6030).
  • Casein Kinase 2 includes the alpha and beta subunits of the human CK2 protein produced in E.coli (New England Biolabs, Beverly, Mass., Cat. #6010).
  • Calmodulin Kinase (calmodulin-dependent protein kinase 2) is a truncated version of the alpha subunit of the rat protein produced in insect cells (New England Biolabs, Beverly, Mass., Cat. #6060).
  • Glycogen Synthase Kinase-3 is the beta isoform of the rabbit enzyme produced in E. coli (New England Biolabs, Beverly, Mass., Cat. #6040).
  • MAP Kinase is the rat ERK-2 isoform containing a polyhistidine tag at the N-terminus produced in E.coli . and activated by phosphorylation with MEK1 prior to purification (BIOMOL, Madison Meeting, Pa., Cat. #SE-137).
  • ERK-1 protein Discontinued from Calbiochem.
  • EGFR epimal growth factor receptor
  • PDGF-R platelet derived growth factor receptor
  • PDGF-R beta subunit kinase domain accesion #M21616.
  • the HER2 (human epidermal growth factor receptor-2) construct contains a polyhistidine tag at the N-terminus followed by 24 additional amino acids and begins at amino acid 676 followed by the remainder of the HER2 cytoplasmic domain.
  • VEGF-R (Biotin)KHKKLAEGSAYEEV-Amide CDK1 (Biotin)KTPKKAKKPKTPKKAKKL-Amide CDK2 (Biotin)KTPKKAKKPKTPKKAKKL-Amide CDK4 (GST)AminoAcids 769-921 of retinoblastoma EGF-R (Biotin)Poly(GT)4:1 Protein Kinase A (Biotin)GRTGRRNSI-Amide PKC (Biotin)RFARKGSLRQKNV-NH2 Casein Kinase 1 (Biotin)KRRRALS(phospho)VASLPGL-Amide Casein Kinase 2 (Biotin)RREEETEEE-Amide Calmodulin Kinase Biotin)KKALRRQETVDAL-Amide GSK-3 Biotin)KRREILSRRP(phospho)SYR-Amide MAP Kinase ERK-1 (Biotin)AP
  • IC 50 data for various kinases are shown in Table 2a through Table 2k.
  • IC 50 values listed as >10 or >100 indicate no observed 50% inhibition at the highest dose tested for the indicated assay, nor was an inhibition maxima observed.
  • Values shown as ⁇ 10 indicate an approximate value based on an observed 50% inhibition. ND means not tested.
  • test compound The ability of a test compound to inhibit the proliferation of cell growth was determined by measuring incorporation of 14 C-labelled thymidine into newly synthesized DNA within the cells. This method was used on cell lines derived from carcinomas originating from several tissues such as HeLa cervical adenocarcinoma (American Type Culture Collection (ATCC), Virginia, Cat.
  • the in vivo effect of a compound on the growth of human tumor cells can be evaluated by implanting human tumor cells into the hindflank of athymic mice and administering test compound to the mice.
  • Human tumor cells originating from a variety of different tumor types, such as A375 human melanoma cells, are implanted subcutaneously into the hindflank of male athymic mice (Charles River) and allowed to establish a sizeable tumor for 6-10 days as determined by caliper measurements.
  • Test compound is then administered by injecting the compound formulated in an appropriate vehicle intraperitoneally into the mice once a day for 30 days.
  • the test compound can also be administered by other routes such as orally, sub cutaneously or by intravenous infusion.
  • the size of the tumor in this study is measured every four days and the degree of inhibition is determined by comparing drug-treated animals to animals that are injected with vehicle only.
  • the synergistic action or enhancement of conventional chemotherapeutic agent by a test compound can also be determined with this model by comparing animals treated with the standard therapy alone to animals treated with test compound plus the same standard therapy. An additive effect on the delay of tumor growth will be observed if synergistic action due to test compound is occurring.

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